基于QM/MM方法研究溶剂对钯催化环加成反应选择性影响的机制

在液相反应中，溶剂不仅会改变反应势垒导致反应速率和方向发生变化，而且有可能参与反应，从根本上改变反应机制。钯催化的环加成反应作为一类重要的金属有机反应，在环状化合物骨架的构建方面发挥了重要作用。实验研究表明，溶剂对该类反应的化学选择性及立体选择性具有显著影响，然而具体的影响机制并不清楚。针对这一问题，申请人将通过采用无溶剂气象相条件、隐式连续溶剂模型、首次尝试使用QM/MM多尺度模拟方法中的显式溶剂模型，结合DFT、高精度从头算方法，对钯催化环加成反应中溶剂对反应选择性影响的机制进行系统的理论与计算研究。确定反应中重要过渡态和关键中间体的结构与能量信息，阐明溶剂影响钯催化环加成反应选择性的内在机制。本项目的研究结果将从本质上揭示溶剂对钯催化环加成反应选择性的影响规律，进一步确立金属有机体系中溶剂效应的最佳计算方法和模型，为设计和探索新的反应类型，促进相关合成方法学的发展提供重要理论指导。

In solution phase reaction, solvent could not only change the reaction barrier that results in change of the reaction rate and pathway, but also could participate in the chemical reaction and fundamentally change the reaction mechanism. Palladium-catalyzed cycloaddition reaction is one of the most important transition metal catalyzed reaction that plays a very important role in the construction of cyclic compounds. Studies have shown that solvents have a significant effect on the activation and stereoselectivity of these reactions. However, the origin of this influence is still not clear. In this project, the applicant will conduct a systematic study on the origin of the solvation effect on the selectivity of palladium-catalyzed cycloaddition reactions. By using gas phase condition, common continuum modeling, and explicit solvation model in QM/MM multi-scale modeling for the first time, in combination with DFT and other advanced ab-initio methods, we will obtain the important transition state and key intermediates involved in the reactions, clarify the intrinsic mechanism and influence of solvent on the mechanism of activation, chemoselectivity, stereoselectivity, and regioselectivity. We will further establish an advanced solvation/catalysis activation model. This study will facilitate the understanding of palladium-catalyzed cycloaddition reactions and the exploration of new synthetic methods to assist and guide experiments.